Multidimensional Apathy in Behavioral Variant Frontotemporal Dementia, Primary Progressive Aphasia, and Alzheimer Disease.

Apathy is prevalent in dementia, such as behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), and Alzheimer disease (AD). As a multidimensional construct, it can be assessed and subsumed under a Dimensional Apathy Framework. A consistent apathy profile in bvFTD and PPA has yet to be established. The aim was to explore apathy profiles and awareness in bvFTD, PPA, and AD. A total of 12 patients with bvFTD, 12 patients with PPA, 28 patients with AD, and 20 matched controls, as well as their informants/carers, were recruited. All participants completed the Dimensional Apathy Scale (DAS), assessing executive, emotional, and initiation apathy subtypes, a 1-dimensional apathy measure, depression measure, and functional and cognitive screens. Apathy subtype awareness was determined through DAS informant/carer and self-rating discrepancy. Apathy profile comparison showed patients with bvFTD had significantly higher emotional apathy than patients with AD (P < .01) and significantly higher apathy over all subtypes than patients with PPA (Ps < .05). Additionally, patients with bvFTD had significantly lower awareness for emotional apathy (P < .01) when compared to patients with AD and PPA. All patient groups had significant global apathy over all subtypes compared to controls. The emergent apathy profile for bvFTD seems to be emotional apathy (indifference or emotional/affective neutrality), with lower self-awareness in this subtype. Further, lower self-awareness for executive apathy (lack of motivation for planning, organization, or attention) differentiates bvFTD from PPA. Future research should investigate the cognitive and neural correlates as well as the practical impact of apathy subtypes.

Validation of The Edinburgh cognitive and behavioural ALS screen (ECAS) in behavioural variant frontotemporal dementia and Alzheimer's disease.

The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was developed to assess cognitive and behavioural changes in an anterior frontotemporal syndrome (executive functions, language, fluency and behaviour), common in Amyotrophic Lateral Sclerosis (ALS) and also assesses posterior cerebral dysfunction (memory and visuospatial abilities). OBJECTIVES: To validate the ECAS in behavioural variant Frontotemporal Dementia (bvFTD) without ALS, as compared with Alzheimer's disease (AD), against comprehensive neuropsychological assessment. Compare its sensitivity to that of the Addenbrooke's Cognitive Examination (ACE-III) and investigate behavioural changes in both types of dementia. METHODS: Retrospective study of 16 people with bvFTD (without ALS), 32 with AD, and 48 healthy controls completed the ECAS, ACE-III and extensive neuropsychological assessment. RESULTS: The ECAS showed higher sensitivity (94%) and marginally lower specificity (96%) than the ACE-III for both the bvFTD and AD groups. The anterior composite subscore was sensitive for bvFTD (94%), and slightly less so for AD (84%), while the posterior composite subscore was sensitive for AD (97%), and less so for bvFTD (75%). All people with bvFTD that were impaired on the ECAS total and anterior composite scores were also impaired on the anterior function's tests of the neuropsychological assessment. A cut-off of four or more behavioural domains affected differentiated well between the bvFTD and AD groups, while a qualitative analysis of the behavioural interview found different themes between groups. CONCLUSIONS: The ECAS is a valid and sensitive assessment for bvFTD without ALS and for AD. The carer behavioural interview makes it particularly suitable to detect behavioural abnormalities related to frontal lobe disorders.

Multidimensional apathy in ALS: validation of the Dimensional Apathy Scale.

AIM: Apathy is a prominent symptom of amyotrophic lateral sclerosis (ALS), but measurement is confounded by physical disability. Furthermore, it has been traditionally measured as a unidimensional symptom despite research demonstrating a multifaceted construct. The new Dimensional Apathy Scale (DAS) has been specifically designed for patients with motor disability to measure 3 neurologically based subtypes of apathy: Executive, Emotional and Initiation. We aimed to explore this behavioural symptom by examining the substructure of apathy in ALS and to determine the reliability and validity of the DAS in patients and their carers. METHOD: Patients and carers were recruited through the national Scottish Motor Neurone Disease Register and were asked to complete the DAS, the standardised Apathy Evaluation Scale, and the Geriatric Depression Scale-Short Form. 83 patients with ALS, 75 carers and 83 sex-matched, age-matched and education-matched controls participated. RESULTS: When compared with healthy controls, patients showed a significant increase in apathy on the Initiation subscale, and were significantly less apathetic on the Emotional subscale. Scores on the DAS patient and carer versions did not significantly differ. Internal consistency reliability, convergent and discriminant validity were found to be good for the DAS subscales. There was no association between the DAS and functional disability using the ALS Functional Rating Scale. CONCLUSIONS: Apathy in ALS is characterised by a specific profile of increased initiation apathy and reduced emotional apathy. The DAS is a reliable and valid measure for the assessment of multidimensional apathy in ALS.

Improved PCR based methods for detecting C9orf72 hexanucleotide repeat expansions.

Due to the GC-rich, repetitive nature of C9orf72 hexanucleotide repeat expansions, PCR based detection methods are challenging. Several limitations of PCR have been reported and overcoming these could help to define the pathogenic range. There is also a need to develop improved repeat-primed PCR assays which allow detection even in the presence of genomic variation around the repeat region. We have optimised PCR conditions for the C9orf72 hexanucleotide repeat expansion, using betaine as a co-solvent and specific cycling conditions, including slow ramping and a high denaturation temperature. We have developed a flanking assay, and repeat-primed PCR assays for both 3' and 5' ends of the repeat expansion, which when used together provide a robust strategy for detecting the presence or absence of expansions greater than ∼100 repeats, even in the presence of genomic variability at the 3' end of the repeat. Using our assays, we have detected repeat expansions in 47/442 Scottish ALS patients. Furthermore, we recommend the combined use of these assays in a clinical diagnostic setting.

The diagnostic utility of 99mTc-HMPAO SPECT imaging: a retrospective case series from a tertiary referral early-onset cognitive disorders clinic.

BACKGROUND/AIMS: Patients with early-onset dementia (EOD) often present atypically, making an accurate diagnosis difficult. Single-photon emission-computed tomography (SPECT) provides an indirect measure of cerebral metabolic activity and can help to differentiate between dementia subtypes. This study aims to investigate the clinical utility of SPECT imaging in the diagnosis of early-onset Alzheimer's disease. METHODS: All patients attending a tertiary referral clinic specialising in EOD between April 2012 and October 2013 were included in the study. Statistical analysis of SPECT patterns with clinical diagnoses, Addenbrooke's Cognitive Examination version 3 scores, and magnetic resonance imaging (MRI) atrophy was undertaken. RESULTS: The results demonstrated a highly significant association between SPECT hypoperfusion patterns and clinical diagnoses. SPECT changes were demonstrated more frequently than MRI atrophy. CONCLUSIONS: The results suggest that SPECT imaging may be a useful adjunct to clinical evaluation and a more sensitive biomarker than standard structural imaging.

Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial.

BACKGROUND: Motor neuron disease represents a group of progressive and incurable diseases that are characterised by selective loss of motor neurons, resulting in an urgent need for rapid identification of effective disease-modifying therapies. The MND SMART trial aims to test the safety and efficacy of promising interventions efficiently and definitively against a single contemporaneous placebo control group. We now report results of the stage two interim analysis for memantine and trazodone. METHODS: MND SMART is an investigator-led, phase 3, double-blind, placebo-controlled, multiarm, multistage, randomised, adaptive platform trial recruiting at 20 hospital centres in the UK. Individuals older than 18 years with a confirmed diagnosis of either amyotrophic lateral sclerosis classified by the revised El Escorial criteria, primary lateral sclerosis, progressive muscular atrophy, or progressive bulbar palsy, regardless of disease duration, were eligible for screening. Participants were randomised (1:1:1) to receive oral trazodone 200 mg once a day, oral memantine 20 mg once a day, or matched placebo using a computer-generated minimisation algorithm delivered via a secure web-based system. Co-primary outcome measures were clinical functioning, measured by rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R), and survival. Comparisons were conducted in four stages, with predefined criteria for stopping at the end of stages one and two. We report interim analysis from the stage two results, which was done when 100 participants per group (excluding long survivors, defined as >8 years since diagnosis at baseline) completed a minimum of 12 months of follow-up for the candidate investigational medicinal products. The trial is registered on the European Clinical Trials Registry, 2019-000099-41, and ClinicalTrials.gov, NCT04302870, and is ongoing. FINDINGS: Between Feb 27, 2020, and July 24, 2023 (database lock for interim analysis two), 554 people with a motor neuron disease were randomly allocated to memantine (183 [33%]), trazodone (185 [33%]), or placebo (186 [34%]). The primary interim analysis population comprised 530 participants, of whom 175 (33%) had been allocated memantine, 175 (33%) had been allocated trazodone, and 180 (34%) had been allocated placebo. Over 12 months of follow-up, the mean rate of change per month in ALSFRS-R was -0·650 for memantine, -0·625 for trazodone, and -0·655 for placebo (memantine versus placebo estimated mean difference 0·033, one-sided 90% CI lower level -0·085; one-sided p=0·36; trazodone vs placebo: 0·065, -0·051; one-sided p=0·24). The one-sided p values were both above the significance threshold of 10%, indicating that neither memantine nor trazodone groups met the criteria for continuation. There were 483 participants with at least one adverse event (145 [77%] on placebo, 170 [91%] on memantine, and 168 [90%] on trazodone). There were 88 participants with at least one serious adverse event (37 [20%] on memantine, 27 [14%] on trazodone, and 24 [13%] on placebo). A total of 11 serious adverse event led to treatment discontinuation. There was no survival difference between comparisons, with 49 deaths in the memantine group, 52 deaths in the trazodone group, and 48 deaths in the placebo group. INTERPRETATION: Neither memantine nor trazodone improved efficacy outcomes compared with placebo. This result is sufficiently powered to warrant no further testing of trazodone or memantine in motor neuron disease at the doses evaluated in this study. The multiarm multistage design shows important benefits in reducing the time, cost, and participant numbers to reach a definitive result. FUNDING: The Euan MacDonald Centre, MND Scotland, My Name'5 Doddie Foundation, and Baillie Gifford.

Brain reserve and physical disability in secondary progressive multiple sclerosis.

Background: The brain reserve hypothesis posits that larger maximal lifetime brain growth (MLBG) may confer protection against physical disability in multiple sclerosis (MS). Larger MLBG as a proxy for brain reserve, has been associated with reduced progression of physical disability in patients with early MS; however, it is unknown whether this association remains once in the secondary progressive phase of MS (SPMS). Our aim was to assess whether larger MLBG is associated with decreased physical disability progression in SPMS. Methods: We conducted a post hoc analysis of participants in the MS-Secondary Progressive Multi-Arm Randomisation Trial (NCT01910259), a multicentre randomised placebo-controlled trial of the neuroprotective potential of three agents in SPMS. Physical disability was measured by Expanded Disability Status Scale (EDSS), 9-hole peg test (9HPT) and 25-foot timed walk test (T25FW) at baseline, 48 and 96 weeks. MLBG was estimated by baseline intracranial volume (ICV). Multivariable time-varying Cox regression models were used to investigate the association between MLBG and physical disability progression. Results: 383 participants (mean age 54.5 years, 298 female) were followed up over 96 weeks. Median baseline EDSS was 6.0 (range 4.0-6.5). Adjusted for covariates, larger MLBG was associated with a reduced risk of EDSS progression (HR 0.84,95% CI:0.72 to 0.99;p=0.04). MLBG was not independently associated with time to progression as measured by 9HPT or T25FW. Conclusion: Larger MLBG is independently associated with physical disability progression over 96 weeks as measured by EDSS in SPMS. This suggests that MLBG as a proxy for brain reserve may continue to confer protection against disability when in the secondary progression phase of MS. Trail registration number: NCT01910259.

Genotype-phenotype characterisation of long survivors with motor neuron disease in Scotland.

BACKGROUND: We investigated the phenotypes and genotypes of a cohort of 'long-surviving' individuals with motor neuron disease (MND) to identify potential targets for prognostication. METHODS: Patients were recruited via the Clinical Audit Research and Evaluation for MND (CARE-MND) platform, which hosts the Scottish MND Register. Long survival was defined as > 8 years from diagnosis. 11 phenotypic variables were analysed. Whole genome sequencing (WGS) was performed and variants within 49 MND-associated genes examined. Each individual was screened for C9orf72 repeat expansions. Data from ancestry-matched Scottish populations (the Lothian Birth Cohorts) were used as controls. RESULTS: 58 long survivors were identified. Median survival from diagnosis was 15.5 years. Long survivors were significantly younger at onset and diagnosis than incident patients and had a significantly longer diagnostic delay. 42% had the MND subtype of primary lateral sclerosis (PLS). WGS was performed in 46 individuals: 14 (30.4%) had a potentially pathogenic variant. 4 carried the known SOD1 p.(Ile114Thr) variant. Significant variants in FIG4, hnRNPA2B1, SETX, SQSTM1, TAF15, and VAPB were detected. 2 individuals had a variant in the SPAST gene suggesting phenotypic overlap with hereditary spastic paraplegia (HSP). No long survivors had pathogenic C9orf72 repeat expansions. CONCLUSIONS: Long survivors are characterised by younger age at onset, increased prevalence of PLS and longer diagnostic delay. Genetic analysis in this cohort has improved our understanding of the phenotypes associated with the SOD1 variant p.(Ile114Thr). Our findings confirm that pathogenic expansion of C9orf72 is likely a poor prognostic marker. Genetic screening using targeted MND and/or HSP panels should be considered in those with long survival, or early-onset slowly progressive disease, to improve diagnostic accuracy and aid prognostication.

The Patient Health Questionnaire (PHQ-9) as a tool to screen for depression in people with multiple sclerosis: a cross-sectional validation study.

BACKGROUND: Depression has a point prevalence of 25% and lifetime prevalence of 50% in people with multiple sclerosis (pwMS). Due to accessibility and brevity, the 9-item Patient Health Questionnaire (PHQ-9) may be a useful tool in clinical practice for screening and monitoring of depressive symptoms in people with MS (pwMS). METHODS: The objective of this study was to evaluate the reliability, validity and acceptability of the PHQ-9 as a screening tool for depressive symptoms in pwMS. PwMS completed online questionnaires at 3 time-points over 4-weeks. The PHQ-9, Multiple Sclerosis Impact Scale (MSIS-29), Centre for Disease Control Health-Related Quality of Life Measure (CDC-HQOL-4) and clinical history. RESULTS: 103 participants completed the PHQ-9 at three time points, 43% were categorised as depressed on at least one response. The PHQ-9 exhibited high internal reliability (Cronbach's α = 0.89), and test-re-test agreement (ICC 0.89, 95% CI 0.85-0.91). Convergent validity was indicated through positive correlation with the mental health items on the MSIS-29 (r = 0.46 and r = 0.50) and CDC-HQOL-4 (r = 0.79 and r = 0.73) at both assessment points. Positive correlations between the PHQ-9 and the MSIS-29 (r = 0.86 and r = 0.84) and CDC-HQOL-4 (r = 0.55 and r = 0.37) physical symptom sub-scores did not indicate divergent validity. 93% of ratings evaluated the PHQ-9 as "Very" or "Completely" acceptable. CONCLUSION: The PHQ-9 is a reliable and valid measure of depressive symptoms in people with MS. Given its accessibility, ease of administration, and acceptability, we recommend the PHQ-9 as a tool to screen for depressive symptoms in people with MS.

Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease.

INTRODUCTION: Motor neuron disease (MND) is a rapidly fatal neurodegenerative disease. Despite decades of research and clinical trials there remains no cure and only one globally approved drug, riluzole, which prolongs survival by 2-3 months. Recent improved mechanistic understanding of MND heralds a new translational era with many potential targets being identified that are ripe for clinical trials. Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART) aims to evaluate the efficacy of drugs efficiently and definitively in a multi-arm, multi-stage, adaptive trial. The first two drugs selected for evaluation in MND-SMART are trazodone and memantine. METHODS AND ANALYSIS: Initially, up to 531 participants (177/arm) will be randomised 1:1:1 to oral liquid trazodone, memantine and placebo. The coprimary outcome measures are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) and survival. Comparisons will be conducted in four stages. The decision to continue randomising to arms after each stage will be made by the Trial Steering Committee who receive recommendations from the Independent Data Monitoring Committee. The primary analysis of ALSFRS-R will be conducted when 150 participants/arm, excluding long survivors, have completed 18 months of treatment; if positive the survival effect will be inferentially analysed when 113 deaths have been observed in the placebo group. The trial design ensures that other promising drugs can be added for evaluation in planned trial adaptations. Using this novel trial design reduces time, cost and number of participants required to definitively (phase III) evaluate drugs and reduces exposure of participants to potentially ineffective treatments. ETHICS AND DISSEMINATION: MND-SMART was approved by the West of Scotland Research Ethics Committee on 2 October 2019. (REC reference: 19/WS/0123) Results of the study will be submitted for publication in a peer-reviewed journal and a summary provided to participants. TRIAL REGISTRATION NUMBERS: European Clinical Trials Registry (2019-000099-41); NCT04302870.

The brief Dimensional Apathy Scale: A short clinical assessment of apathy.

Objective: Apathy is a prominent syndrome across neurodegenerative diseases. The Dimensional Apathy Scale (DAS) assesses three apathy subtypes-executive, emotional, and initiation-and is sensitive and valid in amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease. This study describes the development of the brief DAS (b-DAS), which will enable apathy to be swiftly detected in the clinic.Method: 102 ALS and 102 AD patients' previously collected data were used. Mokken analyses were performed on item-level data of each informant/carer-rated DAS subscale (executive, emotional, and initiation) for the initial scale reduction. Item-total correlational analyses against standard apathy (convergent validity criteria) and depression (divergent validity criteria) measures and qualitative examination of items aided final item selection. Receiver operating curve analysis determined optimal cutoffs for the reduced subscales.Results: Mokken analyses suggested unidimensionality of each DAS subscale. Three items were removed that failed to satisfy monotone homogeneity model requirements, three items were removed due to validity criteria not being met, and six items were removed due to a combination of lower item scalability and item-total correlations. Item-theme examination further reduced the b-DAS to nine items, three per subscale, with a supplemental awareness deficit assessment being added. Sensitivity- and specificity-based optimal cutoffs were calculated for each b-DAS subscale.Conclusions: This study presents the b-DAS, an informant/carer-based robust yet short multidimensional apathy instrument with good convergent and divergent validity, with recommended clinical cutoffs. The b-DAS is appropriate for use in the clinic and for research to quickly and comprehensively screen for apathy subtype impairments.

An epidemiological profile of dysarthria incidence and assistive technology use in the living population of people with MND in Scotland.

Objectives: People with motor neurone disease (pwMND) experience communication impairments due to speech and motor dysfunction. Communication support in the form of Augmentative and Alternative Communication (AAC) in conjunction with Assistive Technology (AT) access methods are available, however, variation in provision care pathways exists across Scotland. We conducted a baseline study of communication support for pwMND in Scotland to inform and improve future service provision.Methods: A cross-sectional population-based study was undertaken. Anonymised demographic and clinical phenotypic data for all pwMND in Scotland were extracted from the Care Audit Research Evaluation of MND (CARE-MND) platform, the National MND Register for Scotland. Additional information for AT loans was provided by the third sector charitable organization MND Scotland (MNDS).Results: In total, 371 pwMND were included, 43% of all pwMND were recorded as having impaired speech (recent ALSFRS-R score assessment [Formula: see text]3) and 69% had been referred to Speech and Language Therapist (SLT) services, although there was variation in referral time from diagnosis date. AAC equipment had been acquired by 17.3% of all pwMND; most commonly iPads and the LightwriterTM speech generating device.Conclusions: Our data highlight a high prevalence of speech impairment in pwMND irrespective of the subtype diagnosis. We therefore recommend standardized care pathways and earlier access to coordinated SLT and Occupational Therapist services to enable prospective and personalized decision making. Our findings further highlight the need for qualitative research to understand the preferences and impact of such interventions from the perspective of the user and their communication partners.

National audit of cognitive assessment in people with pwMND A national audit of cognitive assessment in people with motor neurone disease (pwMND) in Scotland.

Cognitive and behavioral abnormalities are recognized as an integral part of Motor Neurone Disease (MND) and occur at all stages of the disease. The early detection of cognitive and behavioral symptoms in MND is critical. Such symptoms are only reported when we explicitly ask, evaluate, document, and assess. In the National Institute for Health and Care Excellence (NICE) MND guideline (2016), formal cognitive and behavioral assessment is incorporated in MND management and is fundamental to providing appropriate care to pwMND. Cognition is explicitly stated in 14 separate recommendations in the guidelines. The NICE guidelines therefore constitute pre-defined standards which we audited. This audit highlights that health professionals increasingly recognize the significance of cognitive screening in MND and follow more structured approaches in implementing this compared to previous years.

Reliability and validity of the brief dimensional apathy scale.

OBJECTIVE: Apathy is composed of different demotivational subtypes measurable by the dimensional apathy scale (DAS) and can be quickly assessed using the brief DAS (b-DAS). The aim was to determine the reliability and validity of the b-DAS. METHODS: 53 amyotrophic lateral sclerosis (ALS) patients and 53 of their informants were recruited. Informants completed the b-DAS, the original informant/carer-rated DAS and behavioral interview about the patients (i.e., presence of behaviors such as apathy/inertia, loss of sympathy/empathy). Patients completed measures of depression, anxiety, emotional lability, cognitive functioning, and functional disability measures. RESULTS: The b-DAS showed good internal consistency, excellent test-retest reliability, significant positive correlation with the original DAS, and no significant correlations with depression, anxiety, emotional lability, cognitive functioning or functional disability measures. Semi-structured behavior interview showed patients with apathy/inertia had significantly higher b-DAS subscale scores and patients with loss of sympathy/empathy had significantly higher emotional apathy scores only. CONCLUSIONS: The b-DAS is a fast, reliable, and valid instrument for screening apathy subtypes independent of physical disability.

C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts.

OBJECTIVE: We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases. METHODS: We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions. RESULTS: We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10-5; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10-2; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy. CONCLUSIONS: Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.

Changing epidemiology of motor neurone disease in Scotland.

OBJECTIVES: Scotland benefits from an integrated national healthcare team for motor neurone disease (MND) and a tradition of rich clinical data capture using the Scottish MND Register (launched in 1989; one of the first national registers). The Scottish register was re-launched in 2015 as Clinical Audit Research and Evaluation of MND (CARE-MND), an electronic platform for prospective, population-based research. We aimed to determine if incidence of MND is changing over time. METHODS: Capture-recapture methods determined the incidence of MND in 2015-2016. Incidence rates for 2015-2016 and 1989-1998 were direct age and sex standardised to allow time-period comparison. Phenotypic characteristics and socioeconomic status of the cohort are described. RESULTS: Coverage of the CARE-MND platform was 99%. Crude incidence in the 2015-2017 period was 3.83/100,000 person-years (95% CI 3.53-4.14). Direct age-standardised incidence in 2015 was 3.42/100,000 (95% CI 2.99-3.91); in 2016, it was 2.89/100,000 (95% CI 2.50-3.34). The 1989-1998 direct standardised annual incidence estimate was 2.32/100,000 (95% CI 2.26-2.37). 2015-2016 standardised incidence was 66.9% higher than Northern European estimates. Socioeconomic status was not associated with MND. CONCLUSIONS: Our data show a changing landscape of MND in Scotland, with a rise in incidence by 36.0% over a 25-year period. This is likely attributable to ascertainment in the context of improved neurological services in Scotland. Our data suggest that CARE-MND is a reliable national resource and findings can be extrapolated to the other Northern European populations.

Improved survival and 30-day mortality after gastrostomy in Scottish motor neurone disease patients: evidence from a national retrospective cohort study using STROBE criteria.

Objectives: Defining historical changes and outcomes in the use of gastrostomy in the management of Scottish MND patients. Methods: The 1989-1998 and 2015-2016 Scottish national MND cohorts were used to examine the frequency, timing, and survival related to gastrostomy. The cohorts were censored for survival analysis. Results: There were 261 cases, 119 (46%) from the new register (2015-2016) and 142 (54%) from the old register (1989-1999). Percutaneous endoscopic gastrostomy (PEG) tubes were used exclusively in the old register vs. the new register where PEG (45%), Radiologically inserted gastrostomy (RIG) (44%) and a small number of peroral image-guided gastrostomy (PIGG) tubes (11%), p < 0.01 were used. Odds of 30-d mortality in the old register were 2.8 times that in the new register, p < 0.01. Median survival time from gastrostomy was significantly higher in the new register, 2.7 months, p < 0.05. Median survival time from onset was also higher in the new register but non-significant, 3.2 months, p = 0.30. Multivariate analysis identified age at onset (hazard ratio [HR] 1.02 p = 0.01), time from onset to diagnosis (HR 0.74 p < 0.01), subtype of onset (HR 1.52 p = 0.01), with gastrostomy and Riluzole interacting as variables that predict risk of death. Conclusions: Gastrostomy use has increased with techniques changing over time. It is safer and survival time has increased post gastrostomy. Being older and diagnosed more quickly increases risk of death whilst taking Riluzole combined with gastrostomy reduced risk of death. Survival from onset has not significantly changed in Scottish MND patients having gastrostomy.

Regional variation in the incidence rate and sex ratio of multiple sclerosis in Scotland 2010-2017: findings from the Scottish Multiple Sclerosis Register.

BACKGROUND: Fifteen regional studies published over the last six decades surveying prevalence, mortality and hospital admissions have suggested that Scotland is amongst the highest risk nations for multiple sclerosis (MS) in the world. However, substantial intranational variation in rates (between regions) has been described in numerous countries, including in the only previous Scottish national survey, which used hospital admission data, to address this issue. Against this backdrop, the Scottish Multiple Sclerosis Register (SMSR) was established in 2010 to prospectively collect nationally comprehensive incidence data and to allow for regional comparisons. METHODS: Here, we present the SMSR and analyse the variation in crude and age-sex standardized incidence rates, lifetime risk (cumulative incidence), and the sex distribution of cases and rates, between the 14 administrative Health Boards or regions of Scotland: 01 January 2010 to 31 December 2017. RESULTS: The overall incidence rate for Scotland was 8.76/100,000 person-years (standardized: 8.54). Regional incidence rates varied significantly-up to threefold-between Health Boards (p < 1 × 10-13). The national female-to-male sex ratio was 2.3:1, but this too varied regionally (outlier regions result in a range from 1.0 to 4.2:1). Lifetime risk ranged from 19.9/1000 for females in Orkney (58.98°N) to 1.6/1000 for males in the Borders (55.60°N). Comparison with a previous national survey suggests that these differences are longstanding. In 6 of 14 regions the lifetime risk for women exceeds 1%. CONCLUSIONS: This study introduces a national incidence register: a valuable research tool and the result of substantial public investment. The wide variation in incidence rates and sex ratios between regions, in a relatively homogenous population, raises questions for future study.

Clinical audit research and evaluation of motor neuron disease (CARE-MND): a national electronic platform for prospective, longitudinal monitoring of MND in Scotland.

Objectives: Launched in 1989, the Scottish Motor Neuron Disease Register (SMNDR) has provided a resource for prospective clinical data collection. However, in 2015 we aimed to evolve a system to allow: i) A patient-centered approach to care based on recognized standards, ii) Harmonized data sharing between Scottish health professionals in "real-time", iii) Regular audit of care to facilitate timely improvements in service delivery, and iv) Patient participation in a diverse range of observational and interventional research studies including clinical trials. Methods: We developed a standardized national electronic data platform-Clinical Audit Research and Evaluation of MND (CARE-MND) which integrates clinical audit and research data fields. Data completion pre- and post-CARE-MND were compared, guided by recently published National Institute for Clinical Excellence (NICE) recommendations. Statistical difference in data capture between time periods was assessed using Z-test of proportions. Results: Data field completion for the historical 2011-2014 period ranged from 4 to 95%; median 50%. CARE-MND capture ranged from 32 to 98%; median 87%. 15/17 fields were significantly more complete post-CARE-MND (p < 0.001). All MND nurse/allied health specialists in Scotland use the CARE-MND platform. Management of MND in Scotland is now coordinated through a standardized template. Conclusions: Through CARE-MND, national audits of MND care and interventions have been possible, leading to protocols for harmonized service provision. Stratification of the MND population is facilitating participation in observational and interventional studies. CARE-MND can act as a template for other neurological disorders.

Investigating Domain-Specific Cognitive Impairment Among Patients With Multiple Sclerosis Using Touchscreen Cognitive Testing in Routine Clinical Care.

Cognitive dysfunction is present in up to 70% of patients with multiple sclerosis (MS) and has been reported at all stages and in all subtypes of the disease. These deficits have been reported across a variety of cognitive domains, but are generally under-recognized and incompletely evaluated in routine clinical practice. The aim of this study was to investigate the spectrum of cognitive impairment in patients with MS presenting to a specialist MS clinic using the Cambridge Neuropsychological Test Automated Battery (CANTAB), administered on a touchscreen platform. Ninety MS patients completed computerized CANTAB tasks assessing working memory, executive function, processing speed, attention, and episodic memory. Scores were adjusted for age, sex, and level of education and classified as normal or impaired based on comparison with a large normative data pool. We also investigated the impact of clinical and demographic variables which could potentially influence cognitive performance including patient educational level (a proxy for cognitive reserve), disease status (duration, course, and severity of MS), and depression. CANTAB testing detected cognitive impairment in 40 patients (44% of the sample). The most frequently impaired domain was executive function, present in 55% of cognitively impaired individuals. Disease duration and severity were significantly associated with performance across various cognitive domains. Patients with depressive symptoms were also more likely to exhibit impaired processing speed. Results from this study confirm that cognitive impairment is common and occurs across a range of domains among MS patients attending routine clinical visits. CANTAB tasks provide a sensitive and practical approach to cognitive testing in MS patients as part of a holistic patient assessment.